Injury to the renal proximal tubular epithelium (PTE) represents the underlying cause for acute kidney injury (AKI) following exposure to various stresses including ischemia-reperfusion (I/R) and nephrotoxins. Kidney cells possess intrinsic mechanisms that can be activated to protect their survival under stress conditions. Facilitating repair of PTE cells will have beneficial effects in the treatment of AKI; however, the knowledge gap in understanding the mechanisms associated with repair of injury to these cells has been a setback in the development of novel therapies for AKI. Our group previously identified MG53, a novel member of the TRIM family protein, as an essential component of the cell membrane repair machinery. Although native MG53 protein is predominantly expressed in striated muscles, it is also present in the kidney particularly in PTE cells at a low, but significant concentration. PTE cells derived from the Mg53-/- mice are more vulnerable to membrane injury than normal cells, a phenotype that is also observed in striated muscles, suggesting that MG53 contributes to repair of renal epithelial cells. Compared with wild type mice, the Mg53-/- mice develop renal disorder and are more susceptible to I/R- induced AKI. We found that the recombinant human MG53 (rhMG53) protein can cross the glomeruli and target to injury sites on PTE cells to facilitate the renal protective effect against various stresses. Intravenous administration of rhMG53 could protect I/R and cisplatin-induced injury to the kidney in rodent models. These data suggest that upregulating the MG53-mediated repair mechanism in PTE cells may be beneficial in preventing AKI and treating established AKI. Since native MG53 is present in circulation, systemic administration of rhMG53 would be unlikely to induce an immune response, and potentially be a safe biologic approach for treatment of AKI. The long-term goal of this project is to test the hypothesis that MG53 contributes to maintenance of renal function under physiological conditions, and targeting MG53-mediated repair of injury to PTE cells represents an effective means for prevention and treatment of AKI. Two specific aims are proposed: a) to elucidate the mechanism for MG53-mediated membrane repair in maintenance of renal function under physiological and AKI conditions; and b) to conduct proof-of-concept studies on rhMG53- based therapy for prevention or treatment of AKI. Fulfillment of these studies should advance our knowledge on the molecular mechanisms that underlie the protection of renal cells from stress-induced injuries, and help development of novel therapies for prevention and treatment of AKI.